Neural responses to pain and injury as well as to various means of analgesia have profound implications as their regulation ultimately can be shown to affect the course of inflammation and thus become a matter of considerable interest. The ultimate goal is to identify and reveal the mechanisms by which the most conservative means of producing long-lasting analgesia can be achieved. This investigation clarifies the relationships between peripheral nerve injury, neuropathic pain, and inflammation using a rat model in which neural injury has been produced by chronic compression of the DRG by a previously described technique employing the insertion of hollow steel rods implanted into IVF at L4 and L5. A cross-section of previously described behavioral, electrophysiological, biochemical, and histological outcomes will be assessed at varying times following the surgical implants. Specifically, the behavioral out comes will include thermal and mechanical hyperalgesia as determined by the shortened latency and decreased threshold of foot withdrawal to stimulation of the plantar surface by heat or contact. Cytological markers will include increased vascularization and accumulation of glia cells around the neurons. Electrophysiological indicators will be shown by the resting membrane potential, action potential threshold current and repetitive discharge characteristics evoked by depolarizing currents and the spontaneous activity of DRG neurons. Biochemical and molecular manifestations of pain and inflammation will include the proinflammatory cytokines TNF-1 and the IL-1 and IL-6, as well as the anti- inflammatory cytokine IL-10. From 1 to 35 days after surgery, these outcome measures are to be compared in the presence or absence of varying times of delivery and force settings of a commercially available instrument used to achieve spinal manipulation, known as the Activator. Two force settings with adjustments delivered daily after surgery for [a] 3 days followed by 3 or 10 adjustments at intervals of every other day, or [b] 7 days followed by 3 adjustments at intervals of every other day are to be thus evaluated. The overarching goal is to apply these results to the development of guidelines and best practices in everyday clinical applications. PUBLIC HEALTH RELEVANCE: These investigations identify in further detail the links between pain and inflammation and how these processes may be suppressed by a form of instrument-assisted spinal manipulation. In so doing, it may become more apparent how the inhibition of pain necessarily becomes the suppression of inflammation, a potentially life-threatening process. From a practical standpoint, the optimum dosage force, frequency and temporal distribution of manipulations obtained should be useful benchmarks in the development of clinical guidelines and best practices in everyday clinical applications.